Lab News

The Corn lab  held an exciting retreat in Unterwasser (Toggenburg region, St. Gallen) on September 10th and 11th, offering a perfect blend of productivity and engagement. The retreat featured focused writing workshops, sessions on scientific illustration tools, and in-depth discussions on career development, including negotiation skills. Lab members had a valuable opportunity to network, share ideas, and explore future career paths, all while enjoying the beautiful surroundings.

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CRISPR-Cas9 gene editing is widely used to introduce targeted mutations in cells and organisms. During the gene editing process, Cas enzymes induces a double-strand break at a target genomic site that is subsequently repaired by on of two mechanisms: error-prone nonhomologous end joining (NHEJ) that results in genomic insertions and deletions (indels), or templated homology-directed repair (HDR) to precisely insert, delete, or replace a genomic sequence.  Have you ever wondered why CRISPR-Cas mediated HDR editing is so efficient in some cells but terribly inefficient in others? Struggling with gene editing in your cells? We’ve got the solution you’ve been looking for!

We are excited to announce a significant advancement in our understanding of CRISPR-Cas9-mediated HDR through genome-wide screening conducted in Fanconi anemia (FA) patient lymphoblastic cell lines. Our research led by Postdoc Erman Karasu uncovered a single suppressor of CRISPR-Cas9 mediated HDR, revealing that exonuclease TREX1 plays a critical role in reducing HDR efficiency when the repair template is either single-stranded or linearized double-stranded DNA. TREX1 expression serves as a biomarker for CRISPR-Cas9-mediated HDR, and high levels of TREX1, observed in various cell types including U2OS, Jurkat, MDA-MB-231, primary T cells, and hematopoietic stem and progenitor cells (HSPCs), are predictive of poor HDR outcomes. Moreover, we have demonstrated that HDR efficiency can be significantly improved, by 2- to 8-fold, through either knockout of TREX1 or the use of chemically protected single-stranded DNA templates that are resistant to TREX1 activity. Namely, phosphorothioate 3’ end protection is sufficient for fast inexpensive improvements to HDR in contexts with appreciable TREX1 expression. These strategies offer promising avenues for enhancing CRISPR-Cas9–mediated HDR, particularly in cell types with high TREX1 expression.

Overall, our data sheds mechanistic light on why donor template protection increases HDR, provide a concrete biomarker for the targeted use of template protection, and resolve long-standing confusion around why editing works like a breeze in some cells, but fails miserably in others. This breakthrough holds substantial potential for advancing research and therapeutic applications.

For more, check out our paper, it is now out in Nature Biotechnology!

Don’t miss the explainer video highlighting Erman’s work!

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Luca received his Master’s degree in Biological Chemistry from the ETH Zürich in 2024. Luca joined the Corn Lab as a Research Assistant in July 2024; his research interests are focused on the application of the gene editing tool CRISPR to further the understanding of gene expression and the possible influence on the medical field.

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Xinhe (Lily) Zheng received her Bachelor’s degree in Molecular and Cell Biology from UC Berkeley in 2023. Lily joined the Corn lab in early July 2024. For her Master’s thesis she is investigating the dynamics of homology search during homology-directed repair of DNA double-strand breaks. 

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Carolyn received her PhD in molecular oncology from The University of Melbourne in 2021, working with Professor Frédéric Hollande on tumour and immunological heterogeneity in the context of metastatic colorectal cancer. She joined the Corn lab as a postdoctoral researcher in June 2024. Her ongoing research interests include functional cancer (epi)genomics and harnessing next-generation genome editing tools for precision medicine.

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Cells constantly experience DNA damage throughout their lifespan due to a variety of endogenous and exogenous factors. Among the different types of DNA damage, double-stranded breaks (DSBs) are particularly severe and can be detrimental if left unrepaired. Eukaryotes have developed mechanisms to detect and repair such damage, known as the DNA damage response (DDR), which involves hundreds of key players and supporting factors. Are you curious to discover more about DDR? Have a look at latest breakthrough,  led by postdoc Erman Karasu in a collaboration with the Jonas group (IMBB) and Zavolan group (University of Basel).

By utilizing a CRISPR screening system to assay about 18,000 gene knockdowns, we identified new players influencing homology-directed repair (HDR). Among these, we focused on CCAR1, an enigmatic gene whose role in the DDR was not well understood. We found that reducing CCAR1 levels impaired both HDR and the repair of interstrand crosslinks, similar to what occurs when the Fanconi anemia (FA) pathway is inactivated. Interestingly, CCAR1 deficiency leads to FANCA protein depletion without affecting FANCA mRNA or other FA gene mRNAs levels. Instead, CCAR1 ensures FANCA mRNA splicing by suppressing a poison exon inclusion. CCAR1 binds to U2-type spliceosome and acts on multiple splicing sites. This demonstrates that CCAR1 is crucial for proper mRNA splicing. Further analysis showed that CCAR1’s role in mRNA splicing extends beyond FANCA, affecting many genes and ensuring that their mRNAs are correctly processed in both mouse and human cells. Our work highlights CCAR1’s unexpected role in maintaining accurate mRNA splicing, which is essential for proper protein function.

For more info check out our new paper in Molecular Cell!

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The Latsis Symposium on Genome and Transcriptome Engineering, held on June 13-14, 2024 in Zurich, was a remarkable event! This dynamic two-day gathering showcased the latest breakthroughs in genome and transcriptome engineering, uniting experts from academia and industry to share new research and practical applications.

Co-organized by the Corn, Platt, Schwank, and Jinek groups, the symposium covered a wide range of topics from cutting-edge research findings to real-world therapeutic innovations.

We were particularly thrilled with the presentation by our PostDoc John Fielden!

Thanks to all who joined us for this exciting exploration of the future of biomedical science!

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From June 10-12, 2024, the Corn Lab members attended the 14t^h D-BIOL Symposium in Davos. This exciting biannual internal ETHZ event brought together nearly 500 participants, including students, postdocs, professors, and special guests, to share and discuss the latest scientific developments.

A special shout-out to our very own Mathias Muhar and Eric Aird for their fantastic talks!

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Luca Bechter received his Bachelor’s degree in Biology from ETH Zurich in 2022. He is currently enrolled in the Biological Chemistry Master’s program at ETH Zürich. Luca joined the Corn Lab as a Master student in September 2023 and for his Master’s thesis he is investigating transcriptional adaptation resulting from introducing knockouts in human cells.

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Irene received her MSc degree in Medical Biotechnology from the University of Modena and Reggio Emilia (Italy), where she worked on the characterization of the epidermal stemness regulatory network in Epidermolysis Bullosa. Irene joined the Corn Lab as a technical specialist in March 2024; her research interests focus on the therapeutic translation of genome editing technologies.

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